Thomas B. Campbell

Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial

BACKGROUND TMC125 (etravirine) is a non-nucleoside reverse-transcriptase inhibitor (NNRTI) with activity against NNRTI-resistant HIV-1 in phase IIb trials. The aim of DUET-2 is to examine the efficacy, tolerability, and safety of TMC125 in treatment-experienced patients. METHODS In this continuing randomised, double-blind, placebo-controlled, phase III trial, HIV-1-infected patients on failing antiretroviral therapy with evidence of resistance to currently available NNRTIs and at least three primary protease inhibitor mutations were eligible for enrolment if on stable (8 weeks unchanged) antiretroviral therapy with plasma HIV-1 RNA greater than 5000 copies per mL. Patients were randomly assigned to receive either TMC125 (200 mg) or placebo, each given twice daily with darunavir-ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors, and optional enfuvirtide. The primary endpoint was the proportion of patients with confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00255099. FINDINGS 591 patients were randomised and treated (295 patients in the TMC125 group and 296 in the placebo group). By week 24, 51 (17%) patients in the TMC125 group and 73 (25%) in the placebo group had discontinued, mainly because of virological failure. 183 (62%) patients in the TMC125 group and 129 (44%) in the placebo group achieved confirmed viral load below 50 copies per mL at week 24 (difference 18%, 95% CI 11-26; p=0.0003). The type and frequency of adverse events were much the same in the two groups. INTERPRETATION In treatment-experienced patients, treatment with TMC125 led to better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.

Comparison of the Respiratory Microbiome in Healthy Nonsmokers and Smokers

RATIONALE Results from 16S rDNA-encoding gene sequence-based, culture-independent techniques have led to conflicting conclusions about the composition of the lower respiratory tract microbiome. OBJECTIVES To compare the microbiome of the upper and lower respiratory tract in healthy HIV-uninfected nonsmokers and smokers in a multicenter cohort. METHODS Participants were nonsmokers and smokers without significant comorbidities. Oral washes and bronchoscopic alveolar lavages were collected in a standardized manner. Sequence analysis of bacterial 16S rRNA-encoding genes was performed, and the neutral model in community ecology was used to identify bacteria that were the most plausible members of a lung microbiome. MEASUREMENTS AND MAIN RESULTS Sixty-four participants were enrolled. Most bacteria identified in the lung were also in the mouth, but specific bacteria such as Enterobacteriaceae, Haemophilus, Methylobacterium, and Ralstonia species were disproportionally represented in the lungs compared with values predicted by the neutral model. Tropheryma was also in the lung, but not the mouth. Mouth communities differed between nonsmokers and smokers in species such as Porphyromonas, Neisseria, and Gemella, but lung bacterial populations did not. CONCLUSIONS This study is the largest to examine composition of the lower respiratory tract microbiome in healthy individuals and the first to use the neutral model to compare the lung to the mouth. Specific bacteria appear in significantly higher abundance in the lungs than would be expected if they originated from the mouth, demonstrating that the lung microbiome does not derive entirely from the mouth. The mouth microbiome differs in nonsmokers and smokers, but lung communities were not significantly altered by smoking.

Persistence of HIV− Associated Cognitive Impairment, Inflammation and Neuronal Injury in era of Highly Active Antiretroviral Treatment

Objective:To determine whether cognitive impairment and brain injury as measured by proton magnetic resonance spectroscopy (MRS) persist in the setting of HAART. Design:This study is an observational cohort study. Methods:MRS was performed in 268 patients: HIV-negative controls (N = 28), HIV-positive neuroasymptomatic individuals (N = 124), and individuals with AIDS dementia complex (ADC; N = 50) on stable antiretroviral therapy (ART) with a mean duration of infection of 12 years and CD4 cell count of 309 cells/μl. Four metabolites were measured over creatine: N-acetyl aspartate (NAA), marker of neuronal integrity; choline (Cho), myoinositol, markers of inflammation, and glutamate and glutamine (Glx) in the basal ganglia, frontal white matter (FWM), and mid-frontal cortex. Analyses included analysis of variance, analysis of covariance, linear, and nonparametric regression models. Results:Cognitive impairment was found in 48% of HIV-infected individuals. Both HIV-positive groups showed significant increases in myoinositol/creatine or Cho/creatine in all brain regions when compared to controls; a significant decrease in Glx/creatine in the FWM was observed in the neuroasymptomatic group; and only individuals with ADC showed a significant reduction in NAA/creatine, although a significant trend for decreasing NAA/creatine in the basal ganglia was found across the groups. Effects related to aging and duration of infection, but not central nervous system penetration effectiveness were observed. Conclusion:Brain inflammatory changes remain ubiquitous among HIV-infected individuals, whereas neuronal injury occurs predominantly in those with cognitive impairment. Together these findings indicate that despite the widespread use of HAART, HIV-associated cognitive impairment and brain injury persist in the setting of chronic and stable disease.

Alterations in the Gut Microbiota Associated with HIV-1 Infection

Understanding gut microbiota alterations associated with HIV infection and factors that drive these alterations may help explain gut-linked diseases prevalent with HIV. 16S rRNA sequencing of feces from HIV-infected individuals revealed that HIV infection is associated with highly characteristic gut community changes, and antiretroviral therapy does not consistently restore the microbiota to an HIV-negative state. Despite the chronic gut inflammation characteristic of HIV infection, the associated microbiota showed limited similarity with other inflammatory states and instead showed increased, rather than decreased, diversity. Meta-analysis revealed that the microbiota of HIV-infected individuals in the U.S. was most similar to a Prevotella-rich community composition typically observed in healthy individuals in agrarian cultures of Malawi and Venezuela and related to that of U.S. individuals with carbohydrate-rich, protein- and fat-poor diets. By evaluating innate and adaptive immune responses to lysates from bacteria that differ with HIV, we explore the functional drivers of these compositional differences.

Effects of nadir CD4 count and duration of human immunodeficiency virus infection on brain volumes in the highly active antiretroviral therapy era

Cerebral atrophy is a well-described, but poorly understood complication of human immunodeficiency virus (HIV) infection. Despite reduced prevalence of HIV-associated dementia in the highly active antiretroviral therapy (HAART) era, HIV continues to affect the brains of patients with chronic infection. In this study we examine patterns of brain volume loss in HIV-infected patients on HAART, and demographic and clinical factors contributing to brain volume loss. We hypothesized that nadir CD4+ lymphocyte count, duration of HIV infection, and age would be associated with reduced cortical volumes. Volumes of cortical and subcortical regions in 69 HIV-infected neuroasymptomatic (NA) individuals and 13 with at least mild acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) were measured using voxel-based morphometry. Demographic and clinical factors (age, plasma HIV RNA level, current and nadir CD4 counts, duration of infection, central nervous system [CNS] penetration of antiretroviral regimen) along with their interactions were entered into a regression model selection algorithm to determine the final models that best described regional brain volumes. Relative to NA, individuals with ADC exhibited decreased total gray matter and parietal cortex volumes and increased total ventricular volumes. Final regression models showed overall cerebral volume, including gray and white matter volume and volumes of the parietal, temporal, and frontal lobes and the hippocampus, were most strongly associated with disease history factors (nadir CD4 and duration of infection). In contrast, basal ganglia volumes were related most strongly to current disease factors, most notably plasma HIV RNA. These findings indicate that individuals with a history of chronic HIV infection with previous episodes of severely impaired immune function, as reflected by reduced nadir CD4+ lymphocyte count, may be at greatest risk for cerebral atrophy. The pattern of HIV-associated brain loss may be changing from a subcortical to a cortical disease among patients who are largely asymptomatic on HAART.

Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi's sarcoma clinical stage.

ObjectiveTo determine the relationship between human herpesvirus 8 (HHV-8 or Kaposis sarcoma-associated herpesvirus) peripheral blood virus load and Kaposis sarcoma (KS) clinical stage. DesignBlinded, cross-sectional analysis of peripheral blood HHV-8 DNA levels in persons with AIDS-related KS in Harare, Zimbabwe. MethodsSubjects were stratified by KS clinical stage. The amount of HHV-8 DNA in plasma and peripheral blood mononuclear cells (PBMC) was determined by quantitative real-time PCR amplification of the HHV-8 open reading frame 26. ResultsThirty-one HIV-1/HHV-8-coinfected persons were studied: 26 subjects had histologically confirmed KS (one stage II, 11 stage III and 14 stage IV) and five subjects had antibodies to HHV-8 but did not have KS. The age, CD4 lymphocyte count and plasma HIV-1 RNA levels were similar in all groups. HHV-8 DNA was detected in the plasma of all HHV-8-infected subjects (range < 2.4 to 5.2 log10 copies/ml), but plasma HHV-8 DNA levels were not associated with KS disease stage. In contrast, the amount of HHV-8 DNA in PBMC (range < 0.7 to 4.5 log10 copies/μg) was strongly associated with KS clinical stage (P = 0.005). Among stage IV KS cases, there was a linear relationship between plasma and PBMC HHV-8 DNA levels (r2 = 0.42;P = 0.01). ConclusionThe strong association observed between the extent of KS disease and the levels of HHV-8 DNA in PBMC provides further evidence for a relationship between HHV-8 virus load and KS pathogenesis.

Widespread colonization of the lung by Tropheryma whipplei in HIV infection

RATIONALE Lung infections caused by opportunistic or virulent pathogens are a principal cause of morbidity and mortality in HIV infection. It is unknown whether HIV infection leads to changes in basal lung microflora, which may contribute to chronic pulmonary complications that increasingly are being recognized in individuals infected with HIV. OBJECTIVES To determine whether the immunodeficiency associated with HIV infection resulted in alteration of the lung microbiota. METHODS We used 16S ribosomal RNA targeted pyrosequencing and shotgun metagenomic sequencing to analyze bacterial gene sequences in bronchoalveolar lavage (BAL) and mouths of 82 HIV-positive and 77 HIV-negative subjects. MEASUREMENTS AND MAIN RESULTS Sequences representing Tropheryma whipplei, the etiologic agent of Whipples disease, were significantly more frequent in BAL of HIV-positive compared with HIV-negative individuals. T. whipplei dominated the community (>50% of sequence reads) in 11 HIV-positive subjects, but only 1 HIV-negative individual (13.4 versus 1.3%; P = 0.0018). In 30 HIV-positive individuals sampled longitudinally, antiretroviral therapy resulted in a significantly reduced relative abundance of T. whipplei in the lung. Shotgun metagenomic sequencing was performed on eight BAL samples dominated by T. whipplei 16S ribosomal RNA. Whole genome assembly of pooled reads showed that uncultured lung-derived T. whipplei had similar gene content to two isolates obtained from subjects with Whipples disease. CONCLUSIONS Asymptomatic subjects with HIV infection have unexpected colonization of the lung by T. whipplei, which is reduced by effective antiretroviral therapy and merits further study for a potential pathogenic role in chronic pulmonary complications of HIV infection.

Antiviral Activity of Lamivudine in Salvage Therapy for Multidrug-Resistant HIV-1 Infection

BACKGROUND Maximum suppression of virus replication is often not achievable for persons infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). Available data suggest that lamivudine contributes to partial viral suppression, despite the presence of M184V mutations and high-level phenotypic lamivudine resistance. METHODS Selective lamivudine withdrawal was studied in 6 subjects who had incomplete viral suppression during antiretroviral treatment for multidrug-resistant HIV-1 infection. RESULTS Plasma levels of HIV-1 RNA increased to 0.5 log(10) copies/mL above baseline 6 weeks after the withdrawal of lamivudine treatment (P=.04), even though reversion of lamivudine resistance was not yet detected. Early increases in plasma levels of HIV-1 RNA after lamivudine withdrawal were associated with the presence of the T215Y/F mutation and broad phenotypic resistance to nucleoside reverse-transcriptase inhibitors at baseline. Genotypic and phenotypic reversion of lamivudine resistance was detected in 4 subjects 8-14 weeks after withdrawal of lamivudine therapy. The duration of lamivudine withdrawal ranged from 8 to 22 weeks; all subjects resumed lamivudine treatment. Plasma levels of HIV-1 RNA were 0.6 log(10) copies/mL above baseline (P=.03) when lamivudine therapy was resumed. After the resumption of lamivudine treatment, plasma HIV RNA levels decreased to baseline levels in 3 subjects but remained elevated in 3 subjects who had evolution of increased antiretroviral drug resistance during the period of lamivudine withdrawal. Safety concerns raised by this latter finding led to permanent closure of the study. CONCLUSIONS In select cases of multidrug-resistant HIV-1 infection, lamivudine contributes to suppression of HIV-1 replication, despite the presence of M184V mutations and lamivudine resistance.

Association of Functional Impairment with Inflammation and Immune Activation in HIV Type 1–Infected Adults Receiving Effective Antiretroviral Therapy

BACKGROUND The relationships of inflammation, immune activation, and immunosenescence markers with functional impairment in aging human immunodeficiency virus type 1 (HIV-1)-infected persons are unknown. METHODS HIV-infected persons who were aged 45-65 years, had a plasma HIV-1 RNA load of <48 copies/mL, and were receiving antiretroviral therapy underwent standardized functional testing. In a nested case-control analysis, low-functioning cases were matched (1:1-2) by age, sex, and HIV-1 diagnosis date to high-functioning controls. Markers of inflammation, T-cell activation, microbial translocation, immunosenescence, and immune recovery were used to estimate functional status in conditional logistic regression. Primary analyses were adjusted for CD4(+) T-cell count, smoking, and hepatitis. RESULTS Thirty-one low-functioning cases were compared to 49 high-functioning controls. After statistical adjustment, lower proportions of CD4(+) T cells and higher proportion of CD8(+) T cells, higher CD38/HLA-DR expression on CD8(+) T cells, and higher interleukin-6 were associated with a significantly greater odds of low functional status (odds ratio, ≥ 1.1 for all analyses; P ≤ .03). Other inflammatory, senescence, and microbial translocation markers were not significantly different (P ≥ .11 for all analyses) between low-functioning and high-functioning groups. CONCLUSIONS Functional impairment during successful antiretroviral therapy was associated with higher CD8(+) T-cell activation and interleukin 6 levels. Interventions to decrease immune activation and inflammation should be evaluated for their effects on physical function and frailty.

Immune Reconstitution Inflammatory Syndrome Associated with Kaposi Sarcoma during Potent Antiretroviral Therapy

Rapidly progressive Kaposi sarcoma (KS) lesions with lymphadenopathy and tissue swelling occurred in a patient during antiretroviral treatment, despite an increased CD4(+) lymphocyte count and decreased HIV-1 level and KS-associated herpesvirus replication, suggesting immune reconstitution inflammatory syndrome. Inflammation resolved coincident with decreases in the CD4(+) lymphocyte count during paclitaxel treatment, whereas KS cleared only after prolonged antiretroviral therapy and chemotherapy.